Nootropics_Myth or Reality

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Drug Development Research 2:433-439 (1982)

Nootropics: Myth or Reality?S. KanowskiDepartment for Gerontopsychiatry, Free University, West Berlin

ABSTRACTKanowski, S.: Nootropics: Myth or reality? Drug Dev. Res.2:433439, 982.

Through the ages there have been two strong human motivations: to remain on this earthas long as possible, and to maintain or regain ones youth and activities in ones old age.The fountain of youth is an ancient mythological version of this strong desire. The questionarises, whether nootropics is a modern one. For a clear understanding t is necessarytodistinguish between geroprophylactica and gerotherapeutica. The extent to which prom-ising models for the development of gerotherapeutica do exist and the value of currentlyexisting gerotherapeuticawill be points of discussion. Strong emphasis will be givento thedifference between statistical significance and clinical relevance in the clinical evaluationof the latter.Key words: noot r op ica, CBS, geronto lo gy, geroprophylact ics, gerotherapeut ics

INTRODUCTIONFor centuries the main view of old age seems to have been a pessimistic one. In accordancewith that view the last or preterminal phase of our life has been described in such terms as illness,

weakness, and immobility, loss of social relationship, and feedback. Disengagement from realityand activity is considered to be a function of all these impairments, and, in turn, has the functionof preparation for ones ow n dying. No wonder that individuals at any time looked at the last phaseof their lives with great fear and searched around for remedies, like the fountain of youth. Butobviously every remedy recommended so far has failed to satisfy the dream of immortality andeternal youth. In our era, pharmaceutical industry has taken on this dream and is making attemptsto develop a, should we say , dry fountain of youth in form of tablets, capsules, and pow ders. T hequestion arises: Are we still in a state of mythology or can these drugs change reality as we haveso far known it?

Received April 22, 1982; accepted June 12, 1982.Address reprint requests to Prof. Dr. S . Kanowski, Department for Gerontopsychiatry, Reichsstrasse 15,1000Berlin 19, Federal Republic of Germany.

0272-4391/82/0205-0433$02.500 982 Alan R . Liss, Inc.


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434 KanowskiI shall try to answer three questions:Why do people ask for drugs preventing them from or alleviating the burdens of aging and

what are the impairments they feel or fear?Do we have theories of the normal or the pathological aging processes which would allowfor the development of pharmacological models?How effective are the pharmacological agents currently on the market under the namenootropics ?QUESTION ONE

To answer the first question one can begin by analyzing the indications given by the blurbsand advertisements, because it seems reasonable to assume that pharmaceutical sales promotiontries to meet peoples complaints and expectations of miraculous cures. Here are some examplesof the indications in som e of these ads: premature or early fatigue; somatic and psychic decline ofperformance; loss of memory and lack of concentration; depression; prolonged convalescence;disturbances of cerebral metabolism, improvements of disturbed cerebral blood flow; preventionof signs of degeneration and symptoms of old age; lack of drive, e tc. All these indications correspondto a model of a general decline of functions particularly in the CNS during the aging process. Ingerontology this model is well known as the deficit model of old age.On the basis of recent results of psychological research in gerontology the generality of thismodel has been questioned. There is no clear evidence of mental decline as an effect of simplebiological aging; the evidence indicates an impairment of psychomotoric performance which canbe the result of many different factors [Thomae, 19761. What instead transpires from ongoingresearch in this field is a great potential of plasticity among the normal older population [Baltesand Baltes, 19801; that is, given different conditions and situations, the older person may showquite different performances. Based on both mere retest effects as well as training effects inintellectual performance (Fig. 1 ) Baltes and co-workers conclude: w e believe that older individualsgenerally live in a context of cognitive dep rivation. Consequ ently, when it comes to psychom etricintelligence test, older persons are likely to function below their optimal level of performance. Itfollows that relatively short-term behavioral interventions (such as retesting and cognitive training)result in significant improvement [Baltes and Baltes, 19801.What we might conclud e from these research results is that complaints of older people abouta mental decline may be due to a lack of training and stimulation rather than to an assumedbiophysiological aging process. Older people might inadvertently contribute to this deprivation.Since they share the common stereotypes on aging with younger people, they run, all too easily,into the trap of the self-fullfilling prophecy.QUESTION TWO

Biological research as yet has not been too successful in finding or describing significantchanges in the CNS which could be attributed to a pure physiological aging process. Th e rates ofneuronal cell loss and diminution of energy and of transmitter, and nucleic acid metabolism duringthe aging process are neither as consistent nor do they reach such an extent as to explain anunavoidable decline of mental functions. Th us, it does not seem reasonable to expect specific drugeffects on mental performance via changes in neuronal processes. Furthermore, there d o not existreliable and clinically relevant models of aging related to changes in the human brain. The latter,if existing, could provide a solid basis of pharmacological research in this field. Currently thereare no drugs available, however, with the geroprophylactic effects as defined by Coper and K anowsk i[1976].The scene changes when we enter the field of pathological aging, which is the field ofgerontopsychiatry. There is no doubt at all about macro- and microscopical atrophy of brainparenchym indicating the biological basis of this kind of mental impairment in old age. T he chron icorganic brain synd rome (CB S) represents the core sym ptomatology of pathologically induced mentaldecline in old age. It can be measured along two dimensions (Fig. 2): (1 ) impairment of intellectual


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Nootropics: Myth or Reality? 435functions, and (2) personality changes. The former are more easily accessible to quantitativemeasurement than the latter. Disturbances of memory, lack of concentration, disturbances ofthinking and comprehension, of orientation and control of emotion are the main signs of intellectualdysfunction within the context of C B S .It is very well known that the CBS is largely independent of the underlying pathologicprocess. This very unspecifity poses important problems concerning theory and construction ofmodels of the CBS. W e have to consider multiple etiology and pathogenesis of the C B S . At presentthe assumption that disturbances of vigilance regulation might represent a final comm on pathogene ticcourse (Fig. 2) remains speculative. This ambiguous situation has some consequences for phar-macological research as well. For experimental as well as for clinical evaluation of drug effects it

100-52-

Mean Per fo rmance

Fig. 1.as a function of retests in elderly subjects [Bakes and Bake s, 19801.Mean percentage of correct solutions across retest trials of fluid intelligence (figural rela tion s, induction)


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436 Kanowski

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Nootropics: Myth or Reality? 437will be necessary to decide on the criterion level. That is, decisions need to be made whether agiven drug acts on symptom level, syndrome level, or influences pathogenetic mechanisms o r evenetiology. The construction of models of the CBS have to be related to this decision. We have torealize that there are various subsets of the CBS in terms of etiology and pathogenesis with moreor less broad intersections (Fig. 3). Unless a given drug does not influence the final commonpathogenetic pathway-for instance, vigilance regulation-we cannot expe ct that one drug improvesall subsets of CBS.As far as our present knowledge extends, energy, transmitter, and nucleid acid .metabolismare primarily involved albeit to a different degree, in the different structures of CBS or dementia[Hoyer, 19801 and most likely are also differentially linked to the different sym ptoms. A pparently,energy metabolism is primarily associated with the case of cerebrovascular dementia, whereas inthe case of senile dementia dopaminergic transmitter systems seem to be primarily involved. Inaddition, we must acknow ledge interactions between different metabo lic systems-for instance,between energy and transmitter metabolism, as Bowen and Davison [19781 demonstrated.From a clinical and neurophysiological viewpoint there is, indeed, evidence that vigilanceregulation plays an important part in chronic organic brain disease. The spectrum of disturbancesof vigilance reaches from random fluctuationsof wakefulness over states of drowsiness to completeinversions of the sleep-wake c ycle. L ack of concentration and reduced perception and comp rehensionare further indicators of lowered vigilance. Thus, we have at least some hypothetical suppositionsabout which neurophysiological and neurochemical systems might be involved in the d evelopmentof CBS. It seems to be reasonable, therefore, to use such systems as targets for pharmacologicalintervention.

Fig. 3 .hatching.

Total set and some subsets of CBS. Pathogenetic subsets, narrow hatching; etiologic subsets, wide


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438 KanowskiQUESTION THREE

How effective are the nootropic drugs currently on the market? There is no doubt that drugslike hydergine, pyrithioxine, piracetam, and pyritinol influence cerebral functions. Drug influenceson EEG chang es and behavioral changes have been demonstrated in placebo-controlled, double-blind studies. EEG changes all tend toward improvement in vigilance [Bente, 1979, 19801. Be-havioral changes, assessed on the basis of clinical rating scales scored by physicians or nurses,show improvement of patients with chronic organic brain lesions. Thus drug effects can be takenfor granted although the mode of pharmacodynamic action of these drugs remains as yet widelyunknown. For instance, McDonald [1979], when reviewing 26 clinical studies, comes to theconclusion that Hydergine does produce some global improvement . . . an d . . . favorably in-fluences certain aspects of cognitive functioning, e . g ., c onfusion, m ental alertness, impairmentof recent memory, disorientation, in elderly institutionalized patients as assessed by subjectiveclinical rating scales. Th e same could be said for piracetam [Bente et al., 19781 or the other drugsjust mentioned. Why, then, are we dissatisfied with the clinical efficacy of nootropics? Let memention three points that seem critical to me.

(1) All drugs available do not have a reliable effect. Some patients do respond favorablyand others not at all. The lack of reliability is demonstrated also by the fact that the differencesbetween verum and placebo effects vary between 15 and 20% for all drugs. Furthermore, as ofnow, a clear correlation between the different test or behavior parameters influenced by the drugshas not been established.

(2) Presently it is not possible to delineate clear-cut differential indications in terms offunctional disabilities or nosologic entities or metabolic syndromes for any of the drugs.

(3) There is an important difference between statistical significance and clinical relevance.It may well be that a given drug improves the patients ab es in the digit span test by 1 to 2points in 70% of the cases, whereas a placebo effect is present only in 50% of the control group.This difference may be statistically significant. However, this result tells us nothing or little about

the patient himself or those who care for him see any reliable and relevants in dealing with daily life situations.Coming back to our general question of whether nootropics are myth or reality, what con-Nootropics are gerotherapeutics but not geroprophylactics.CBS can be considered the main indication of nootropics since impairment of vigilanceseems to be a general factor in the pathogenesis of CBS and most of the drugs dealt with hereexert a vigilance stimulating effect. Other sym ptoms also show improvement but less consistently.At the present nootropics must be regarded as drugs with established action upon cerebralfunctions but rather weak and instable improvement in psychometric and behavioral parameters.These drug effects seem to be weak particularly when compared with the severe and frequently

progressive course of chronic organic brain diseases.In cases of dementia, particularly in those of primary or secondary degenerative origin,where we have no efficient therapeutic principles besides cardiovascular therapy, nootropics canbe regarded and used as a supplementary therapy. Their application, however, should not preventextensive differential diagnostics. The latter assists in the search for treatable etiologies in the casesof secondary dementias and will yield a basis for a fundamental therapy ruled by principles ofinternal medicine. The use of nootropics, furthermore, will not replace or substitute for goodpsychosocial guidance of the patient and his often severely burdened family.REFERENCESBaltes, P.B. and Baltes, M. : Plasticity and variability in psychosocial aging: Methodological and theoreticalissues. In G. E . Gurski (ed): Determining the Effects of Agin g on the Central Nervous System. Berlin:Schering AG, 1980, pp. 41-66.Bente, D ., Glatthaar, G ., Ulrich, G and Lewinsky, M.: Piracetam and Vigilanz. Arzneim.-ForschJDrug Res.

clusions might be drawn?

28: 1529-1530, 1978.


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Nootropics: Myth or Reality? 439Bente D.: Vigilance and evaluation of psychotropic drug effects on EEG. Pharmakopsychiatr. Neuropsycho-Bente, D. :Moglichkeiten und Gren zen der Elektroenzephalographie in der geriatrisch-pharmakotherapeutischenForschung. Vortrag aus dem 7. Rothenburger Gesprach vom 7./8. 11. 1980. F. K . Schattauer-Verlap,in press.Bowen, D.M . and Davison, A.N .: Biochemical changes in the normal ag eing brain and in dementia. In Isaacs,B. (ed): Recent Advances in Geriatric Medicine. Edinburgh, London, New York: Churchill Living-stone, 1978.Coper, H. and Kanowski, S.: Geriatrika: Theoretische Grundlagen, Envartungen, P riifung, Kritik. HippokratesHoyer, S .:Pathophysiologische M uster der zerebralen Insuffizienz im A lter. Vortrag aus dem 7. Roth enbu rgerMcDonald, R.J.: Hydergine: A review of 26 clinical studies. Pharmakopsychiatr. Neuropsychopharmakol.12:Thomae, H.: Patterns of Aging. Findings from the Bonn Longitudinal Study of Aging. Basel: S. Karger

pharmakol. 12: 137-14, 1979.

47: 303-319, 1976.Gesprach vom 7.03. 11. 1980 . F. K . Sch attauer-V erlag, in press.407422, 1979.Verlag, 1976.

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